1. Field of the Invention
This invention relates to a process for preparing cardiotonically active 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinonitriles and to intermediates used therein.
2. Information Disclosure Statement
Lesher and Philion U.S. Pat. No. 4,313,951, issued Feb. 2, 1982 and based on application Ser. No. 194,461, filed Oct. 20, 1980, in turn a continuation-in-part of its copending application Ser. No. 97,504, filed November 26, 1979 and now abandoned, discloses, inter alia, the process for preparing a 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinonitrile by first reacting a pyridinylmethyl lower-alkyl ketone with dimethylformamide di-(lower-alkyl) acetal to produce a 1-(pyridinyl)-2-(dimethylamino)ethenyl lower-alkyl ketone, then reacting said ketone with cyanoacetamide and acidifying the reaction mixture. The same process is disclosed, inter alia, in Lesher, Opalka and Page U.S. Pat. No. 4,276,293, issued June 30, 1981 and based on application Ser. No. 135,211, filed Mar. 28, 1980.
Opalka and Lesher U.S. Pat. No. 4,223,149, issued Sept. 16, 1980, discloses and claims the process for preparing a 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinonitrile by reacting alpha-(pyridinyl)-beta-[di-(lower-alkyl)amino]-acrolein with malononitrile in a lower-alkanol.
Nicholl et al. U.S. Pat. No. 2,824,121, issued Feb. 18, 1958, discloses and claims an improved process for preparing "oxy alkylidene compounds" using a weakly acid compound as catalytic agent, e.g., zinc chloride, the process being particularly useful in preparing ethoxymethylene malonic diethyl ester by reaction of diethyl malonate and triethyl orthoformate in the presence of acetic anhydride and catalytic amounts of zinc chloride.
Mezheritskii et al., Russian Chemical Reviews 42 (5), 392, 399-402 and 410 (1973), in a review article entitled "The Properties of Orthoesters and Their Applications in Organic Syntheses" has a section (pp. 399-402) re "VIII. Reactions of Orthoesters with Substances Containing An Active Methylene Group". Shown inter alia is the reaction of diethyl malonate with triethyl orthoformate by heating the reactants in the presence of excess acetic anhydride to produce diethyl ethoxymethylenemalonate.
Singh copending U.S. patent application Ser. No. 303,178, filed Sept. 17, 1981, issued Aug. 31, 1982 as U.S. Pat. No. 4,347,363, discloses and claims the process for preparing 1,2-dihydro-6-methyl-2-oxo-5-(pyridinyl)nicotinonitriles by reacting a pyridinylmethyl methyl ketone with ethoxymethylenemalononitrile.
Singh copending U.S. patent application Ser. No. 381,062, filed May 24, 1982 now U.S. Pat. No. 4,413,127, discloses and claims the process for preparing 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinonitriles by reacting 2-(lower-alkoxy)-1-pyridinyl)ethenyl lower-alkyl ketone with malononitrile in a lower alkanol.